Antifungal Prophylaxis in Acute Myeloid Leukemia

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Yoav Golan, MD, MS, FIDSA, attending physician and associate professor of medicine at Tufts University School of Medicine, Boston, MA, identifies problematic fungal pathogens and appropriate antifungal prophylactic measures in the setting of acute myeloid leukemia (AML).

There is a high risk of infection in AML patients, and as a result, this determines, to a large extent, the outcome of therapy. In addition, in terms of fungal infection, it’s very hard to make a diagnosis in those patients. Thus, anti-infective prophylaxis is endorsed by several organizations in the United States and elsewhere. And some of the most commonly used guidelines are the guidelines produced by the Infectious Disease Society of America (IDSA) and by NCCN. Those guidelines clearly define the patient population that should be receiving anti-infective and also suggest what anti-infective should be used. As we discussed earlier, patients at high risk for severe neutropenia or prolonged neutropenia should receive antimicrobial prophylaxis. Because those patients are at risk of not just bacterial infections, but also some viral infections and fungal infections, they should get anti-infective therapy that will protect them from all those three components. We already discussed the principles of antibacterial prophylaxis. It is important to remember that patients who undergo chemotherapy and are immunocompromised are at high risk for viral infections, particularly those that belong to the herpes family of viruses, including HHV1, 2, as well as Varicella zoster, and cytomegalovirus (CMV). So the prophylaxis should target those viruses.

In addition to that, antifungal prophylaxis is of particular importance as it is hard to make the diagnosis of fungal infections and they are prevalent on our bodies and in the environment. The recommendation for antifungal prophylaxis is for high-risk patients, and the duration of therapy is similar to that of anti-bacterials. It starts with the occurrence of neutropenia or with high-dose chemotherapy, and ends typically about a week after the resolution of neutropenia.

When focusing on antifungal prophylaxis for AML patients, it is important to understand the type of fungi that typically cause infections in those patients. Those fungi are typically divided into molds and yeasts. The most common yeast that we see in AML patients is actually Candida, a different species of Candida. And the reason that we see this Candida so often is because it’s a common colonizer of humans in general and for those who receive antibiotics for a long period of time in particular. Those Candida species colonize the skin and the gastrointestinal tract and any breakage in the skin or the gastrointestinal tract mucosa is a risk factor for their invasion. As you know, AML patients have many risk factors for violating the integrity of those membranes, and that’s the reason they are at high risk for invasive Candida infections. One factor that increases their risk is the existence of a vascular catheter that remains in place for a long period of time.

Another group of fungi that is prevalent in those patients are the molds, and, of the molds, the one of major concern is Aspergillus. The reason Aspergillus is a problematic pathogen is because it’s very ubiquitous in the environment. We commonly inhale Aspergillus, and data suggests that the most common mold infection in AML patients is Aspergillus. There are several different species of Aspergillus that respond to different anti-Aspergillus therapy and that needs to be appreciated as well.

Other fungi of the mold group that have been emerging in some centers over the past decade or so are Mucorales. These include some of the fungi that are hardest to treat, including mucormycosis and zygomycosis as well. Other fungi that we see every once in a while include Cryptococcus which is a yeast that’s ubiquitous in the environment, and then there are other fungi that are seen less frequently for which we don’t have good antibiotic or antifungal approaches.

The principle of antifungal prophylaxis and the benefit from such prophylaxis was first shown in studies that were conducted more than 20 years ago that showed that when patients were randomized to antifungal prophylaxis versus placebo, the risk of invasive fungal infections decreased in those that received antifungal prophylaxis, and the mortality decreased as well. This established the importance of antifungal therapy. Since that time, the discussion is not about whether someone should get antifungal therapy but rather what should be the best choice for antifungal therapy. Based on what we discussed on types of fungi that can put someone at risk of invasive fungal infection, one would understand that it is important to equally prevent invasive Candida infections as well as invasive mold infections, particularly invasive Aspergillosis. Therefore, it is important to use an agent that can prevent and has activity for both of those different types of pathogens. Some of the antifungals that we’ve been using for therapy, including amphotericin and different lipid preparations of amphotericin are toxic to different organs, in particularly the kidneys, and therefore are not good candidates for antifungal prophylaxis because prolonged exposure will result in high toxicity rates. Others are only given intravenously and are somewhat less convenient to patients, particularly when they are out of the hospital as compared to those that were also available orally.

Among the most commonly used antifungal agents in prophylaxis are fluconazole, itraconazole, voriconazole, and posaconazole. They differ in their ability to prevent Candida and mold infections, and some of them have limited activity against molds and this particularly focuses on fluconazole.